Fluorothiophene derivatives, process for preparing them and pharmaceutical compositions containing them

Abstract

The invention provides compounds of Formula (I), stereoisomers thereof, or pharmaceutically acceptable salts of said compounds or stereoisomers wherein R1 and R2 are as defined herein as well as compositions comprising the same, processes for making the same, and methods of using the same to treat a variety of diseases, including, those requiring interaction with metalloproteases, and more specifically with macrophage metalloelastase (MMP-12), and for the prevention and treatment of respiratory pathologies such as chronic obstructive bronchopneumopathy (COPD), emphysema, chronic bronchitis, chronic pulmonary inflammation, asthma, cystic fibrosis, acute respiratory distress syndrome (ARDS), respiratory allergies including allergic rhinitis, and also diseases associated with the production of TNFα including severe fibrotic pulmonary disease, pulmonary sarcoidosis and silicosis. The compounds of the present invention also show inhibitory activity on metalloprotease-13 (MMP-13), making them useful for the treatment of pathologies involving this enzyme, such as cancer, osteoporosis, osteoarthritis, arthritis, rheumatoid arthritis, atherosclerosis, multiple sclerosis and cardiac insufficiency.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       a steroisomer thereof, or a pharmaceutically acceptable salt of said compound or said steroisomer, wherein: 
 R 1  is halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio or —R 3 ;  
 R 2  is -C 1 -C 4 )alkylenyl-R 4  wherein said (C 1 -C 4 )alkylenyl is optionally and independently substituted with carboxyl, carboxy(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyloxycarbonyl, (C 1 -C 6 )alkyloxycarbonyl(C 1 -C 6 )alkyl-, aminocarbonyl or aminocarbonyl(C 1 -C 6 )alkyl, wherein said amino from aminocarbonyl or aminocarbonyl(C 1 -C 6 )alkyl is optionally and independently substituted with one to two (C 1 -C 6 )alkyl;  
 R 3  is phenyl, cyclohexyl or heterocycle, optionally substituted with one to two substituents, independently selected from halogen, halo(C 1 -C 6 )alkyl-, halo(C 1 -C 6 )alkoxy-, (C 1 -C 6 )alkyl, cyano, cyano(C 1 -C 6 )alkyl-, hydroxyl, (C 1 -C 6 )alkoxy, phenoxy, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkylcarbonyl, benzoyl, hydroxy(C 1 -C 6 )alkyl-, or amino, said amino optionally and independently substituted with one to two (C 1 -C 6 )alkyl;  
 R 4  is phenyl, cyclohexyl or morpholin-4-yl, optionally and independently substituted with one to two halogen, —OR 5 , —CO 2 R 5  or —W—CO 2 R 5 ;  
 R 5  is hydrogen or (C 1 -C 6 )alkyl; and  
 W is (C 1 -C 6 )alkylenyl.  
 
     
     
         2 . A compound of  claim 1  wherein R 1  is located in the para position, or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.  
     
     
         3 . A compound of  claim 1  wherein R 1  is trifluoromethoxy, 4-acetylphenyl, 4-pyridyl, 3-pyridyl, N-pyrrolidinyl, 1-methylpyrrol-3-yl, 3,6-dihydro-2H-pyrid-1-yl, 2-hydroxyphenyl or 2-hydroxy-4-pyridyl, or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.  
     
     
         4 . A compound of  claim 3  wherein R 1  is trifluoromethoxy, 4-acetylphenyl or 4-pyridyl, or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.  
     
     
         5 . A compound of  claim 1  wherein R 4  is cyclohexyl substituted in position 4- with a carboxyl group, or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.  
     
     
         6 . A compound of  claim 5  wherein said carboxyl is trans, or a pharmaceutically acceptable salt of said compound.  
     
     
         7 . A compound of  claim 1  wherein R 2  is -methylenyl-R 4  wherein said methylenyl is substituted with carboxymethyl or aminocarbonylmethyl and wherein R 4  is phenyl, or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.  
     
     
         8 . A compound of  claim 6  wherein the carbon atom bearing R 4  is (R) absolute configuration, or a pharmaceutically acceptable salt of said compound.  
     
     
         9 . A compound selected from: 
 trans-4-({[5-fluoro-4-(4-trifluoromethoxyphenyl)thien-2-yl]carboxamido}methyl)cyclohexanecarboxylic acid;    trans-4-({[5-fluoro-4-(4-[4-acetylphenyl]phenyl)thien-2-yl]carboxamido}methyl)cyclohexanecarboxylic acid;    3-(R)-phenyl-3-({5-fluoro-4-[4-(4-acetylphenyl)-phenyl]thien-2-yl}carboxamido)propanoic acid;    3-(R)-phenyl-3-({5-fluoro-4-[4-trifluoromethoxyphenyl]thien-2-yl}carboxamido)propanoic acid;    3-(R)-phenyl-3-({5-fluoro-4-[4-(4-acetylphenyl)phenyl]thien-2-yl}carboxamido)propanamide; or    3-(R)-phenyl-3-({5-fluoro-4-[4-(4-pyridyl)-phenyl]thien-2-yl}carboxamido)propanoic acid hydrochloride; or    a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.    
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.  
     
     
         11 . A method of treating pathologies requiring the action of a metalloprotease-12 or a metalloprotease-13 inhibitor in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, or a pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.  
     
     
         12 . A method of  claim 11  wherein said pathology requires the action of a metalloprotease-12 inhibitor.  
     
     
         13 . A method of treating chronic obstructive bronchopneumopathy (COPD), emphysema, chronic bronchitis, chronic pulmonary inflammation, asthma, mucoviscidosis, acute respiratory distress syndrome (ARDS), respiratory allergies including allergic rhinitis, and also diseases associated with the production of TNFα, including severe fibrotic pulmonary disease, pulmonary sarcoidosis or silicosis in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, or a pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.  
     
     
         14 . A method of treating cancer, osteoporosis, osteoarthritis, arthritis, rheumatoid arthritis, atherosclerosis, multiple sclerosis or cardiac insufficiency in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, or a pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.  
     
     
         15 . A method of treating chronic obstructive bronchopneumopathy, emphysema or chronic bronchitis in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, or a pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.  
     
     
         16 . A method of treating tobacco-related emphysema in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, or a pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.  
     
     
         17 . A method of treating asthma in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, or a pharmaceutical composition comprising a compound of  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and a pharmaceutically acceptable carrier, vehicle or dilluent.